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Journal of Virology, July 2002, p. 7000-7009, Vol. 76, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.14.7000-7009.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

Gustavo H. Kijak,1 Viviana Simon,2 Peter Balfe,3 Jeroen Vanderhoeven,2 Sandra E. Pampuro,1 Carlos Zala,4 Claudia Ochoa,4 Pedro Cahn,4 Martin Markowitz,2 and Horacio Salomon1*

National Reference Center for AIDS, Department of Microbiology, School of Medicine, University of Buenos Aires,1 the Huesped Foundation, Buenos Aires, Argentina,4 Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York,2 Department of Virology, Windeyer Institute, Royal Free and University College Medical School, London, United Kingdom3

Received 11 February 2002/ Accepted 22 April 2002

The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.

* Corresponding author. Mailing address: Departamento de Microbiología, Facultad de Medicina, U.B.A., Paraguay 2155 piso 11, (1121) Buenos Aires, Argentina. Phone: 54-11-4508-3689. Fax: 54-11-4508-3705. E-mail: hsalomon{at}fmed.uba.ar.

Journal of Virology, July 2002, p. 7000-7009, Vol. 76, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.14.7000-7009.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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